Details

Autor(en) / Beteiligte

• Thériault, Sébastien
• Dina, Christian
• Messika-Zeitoun, David
• Le Scouarnec, Solena
• Capoulade, Romain
• Gaudreault, Nathalie
• Rigade, Sidwell
• Li, Zhonglin
• Simonet, Floriane
• Lamontagne, Maxime
• Clavel, Marie-Annick
• Arsenault, Benoit J
• Boureau, Anne-Sophie
• Lecointe, Simon
• Baron, Estelle
• Bonnaud, Stéphanie
• Karakachoff, Matilde
• Charpentier, Eric
• Fellah, Imen
• Roussel, Jean-Christian
• Philippe Verhoye, Jean
• Baufreton, Christophe
• Probst, Vincent
• Roussel, Ronan
• Redon, Richard
• Dagenais, François
• Pibarot, Philippe
• Mathieu, Patrick
• Le Tourneau, Thierry
• Bossé, Yohan
• Schott, Jean-Jacques

Titel

Genetic Association Analyses Highlight IL6 , ALPL , and NAV1 As 3 New Susceptibility Genes Underlying Calcific Aortic Valve Stenosis

Ist Teil von

• Circulation. Genomic and precision medicine, 2019-10, Vol.12 (10), p.e002617-e002617

Ort / Verlag

United States: American Heart Association

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• Calcific aortic valve stenosis (CAVS) is a frequent and life-threatening cardiovascular disease for which there is currently no medical treatment available. To date, only 2 genes, and , have been identified as causal for CAVS. We aimed to identify additional susceptibility genes for CAVS. A GWAS (genome-wide association study) meta-analysis of 4 cohorts, totaling 5115 cases and 354 072 controls of European descent, was performed. A TWAS (transcriptome-wide association study) was completed to integrate transcriptomic data from 233 human aortic valves. A series of post-GWAS analyses were performed, including fine-mapping, colocalization, phenome-wide association studies, pathway, and tissue enrichment as well as genetic correlation with cardiovascular traits. In the GWAS meta-analysis, 4 loci achieved genome-wide significance, including 2 new loci: (interleukin 6) on 7p15.3 and (alkaline phosphatase) on 1p36.12. A TWAS integrating gene expression from 233 human aortic valves identified (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of in valve tissues. Fine-mapping identified rs1800795 as the most likely causal variant in the locus. The signal identified colocalizes with the expression of the RNA antisense in various tissues. Phenome-wide association analyses in the UK Biobank showed colocalized associations between the risk allele at the lead variant and higher eosinophil count, pulse pressure, systolic blood pressure, and carotid artery procedures, implicating modulation of the IL6 pathways. The risk allele at the lead variant colocalized with higher pulse pressure and higher prevalence of carotid artery stenosis. Association results at the genome-wide scale indicated genetic correlation between CAVS, coronary artery disease, and cardiovascular risk factors. Our study implicates 3 new genetic loci in CAVS pathogenesis, which constitute novel targets for the development of therapeutic agents.